The present invention relates generally to treatment of refractory microbial infections and, more specifically, to a method and composition for cell-based immunotherapy that can recapitulate neutrophil functions in neutropenic individuals afflicted with a microbial infection.
Candida is a major cause of morbidity and mortality in patients with cancer or neutropenia. Candida is an opportunistic fungal pathogen that has become a major cause of nosocomial infections in the United States and worldwide. Candida species are now the fourth most frequent nosocomial bloodstream isolates, surpassing the incidence of bacteremia caused by Escherichia coli or Klebsiella species.
Neutropenia is a major risk factor for the development of disseminated candidiasis. Neutropenia refers to an abnormally low number of neutrophils in the blood. Neutrophils, a type of white blood cell, help fight bacterial infections. A recent survey found that the incidence of disseminated candidiasis in patients with cancer was 70 per 100,000 people in the city of San Francisco, ten-fold higher than the overall population-based incidence. Several other studies have reported an overall incidence of disseminated candidiasis of 2-6% in patients with cancer or neutropenia. Therefore, approximately 28,000 to 84,000 cases of disseminated candidiasis occur per year in the 1.4 million cancer patients in the United States.
Even with antifungal therapy, disseminated candidiasis has an unacceptable attributable mortality of 50% in myeloablated patients. The mortality of Candida sepsis is also greater than 50%, and is therefore higher than the mortality from sepsis due to Pseudomonas aeruginosa, Staphylococcus aureus, or E. coli. Furthermore, resistance to conventional antifungal therapies among Candida isolates is rising, increasing the need for therapeutic modalities for candidal infections, in particular for patients with cancer or neutropenia.
The primary predictor of survival of neutropenic patients with hematogenously disseminated fungal infections is the duration of neutropenia rather than the type and dose of antifungal given. Thus, strategies designed to shorten the duration of neutropenia would logically improve survival. Unfortunately, while administration of myeloid growth factors, such as granulocyte-colony-stimulating-factor (G-CSF), decreases the incidence of infection by shortening the duration of neutropenia, it does not improve survival once infections develop. This lack of efficacy is likely because the effect of a growth factor depends on the ability of a marrow-ablated host to rapidly produce new phagocytes.
Since survival of hematogenously disseminated infections is linearly related to the patient's granulocyte count, exogenous replacement of phagocytes would seem to offer tremendous potential in the therapy of invasive fungal infections. Although granulocyte transfusion is a logical therapeutic option for neutropenic patients with refractory infections, significant technical barriers have prevented its wide-spread use. First, harvesting of sufficient neutrophils to mediate a protective effect is difficult to achieve. Second, the harvesting procedure can cause hemolysis, anaphylaxis, and intravascular volume shifts in donors. Third, ex vivo neutrophils undergo rapid apoptosis, and very quickly lose their ability to chemotax and to kill phagocytized organisms. Notably, this loss of microbicidal activity is particularly severe for killing of Candida as compared to smaller bacterial organisms. Fourth, clinically significant numbers of red blood cells, lymphocytes, platelets, and donor alloantibodies inevitably contaminate even the most pure neutrophil harvests. Therefore, the donor pool is limited by the need to cross-match blood types, and neutropenic recipients may be at risk for graft-versus-host disease (GVHD) from transfused lymphocytes. Of particular importance is that GVHD seen in recipients of granulocyte transfusions is strictly caused by lymphocyte contamination of the transfusate, as phagocytes do not mediate GVHD by themselves.
Thus, there exists a need to garner the therapeutic benefit of neutrophil transfusions but avoid the above obstacles. The present invention satisfies this need and provides related advantages as well.